Since graduating college 14years ago, I have committed myself to a career in academic biomedical research. As a PhD student at New York University in the 1990s, I worked on innate immune responses to oacterial pathogens. After completing medical school with high honors in 2001, I trained in both Internal Medicine and Rheumatology. Two years ago, I decided to pursue the post-doctoral phase of my career with Dr. Laurie Glimcher, a world-renowned immunologist and transcription factor biologist. In Dr. Glimcher's lab, I have developed a keen interest in bone resorption by osteoclasts. Dysregulation of osteoclasts contributes to the pathogenesis of musculoskeletal disorders that I see in my weekly rheumatology clinic, such as osteoporosis and inflammatory arthritis. Nuclear Factor of Activated T-cells (NFATs) are a family of transcription factors important for cellular differentiation pathways and have been implicated in osteoclastogenesis. We generated a murine conditional knockout of NFATd using Cre-loxP technology. Deletion of NFATd results in osteopetrosis and a defect in osteoclastogenesis. In Aim 1, the role of NFATd in osteoclasts is explored under physiologic conditions and in a model of glucocorticoid-induced osteoporosis. We have recently discovered that in the absence of NFATd, osteoclast precursors make osteoprotegerin, a potent inhibitor of osteoclast differentiation. In Aim 2, the mechanism and consequence of this observation is explored. Lastly, a high throughput screen using RNAi technology has been initiated to identify novel regulators of osteoclast differentiation. Aim 3 seeks to validate the "hits" identified in the initial screen and generate a list of targets to explore during the impendent phase of my career. Dr. Glimcher's lab and the Harvard University Biomedical community is the ideal setting to pursue these ambitious projects. Expertise in skeletal biology surrounds us and I have established the appropriate mentors and collaborators. These experiments and my career development plan will train me in the techniques needed to direct a laboratory focused on elucidating the mechanisms of osteoclast development and pathologic bone destruction. Osteoporosis is a devastating disease that causes brittle bones and afflicts millions of Americans. The osteoclast is the only cell capable of destroying bone. This grant seeks to define the genes that regulate the development and function of the osteoclast.